The present disclosure relates generally to pharmaceutical formulations. More specifically, the present disclosure relates to stable pharmaceutical formulations and methods of making the stable pharmaceutical formulations.
The use of freezing in the preservation of pharmaceutical agents is known. One example of a frozen pharmaceutical agent is ceftriaxone sodium, which is stable for at least 18 months if stored at or below −20° C. The advantage of a frozen pharmaceutical, compared to a lyophilized or powdered drug for reconstitution, lies in its ease of use. The frozen formulation can be thawed and administered as is to the patient without need for further dilution. This also reduces the potential for medication errors and contamination due to manipulation by the clinician. Nonetheless, for some very unstable drugs, freezing a drug solution can cause degradation of the drug. This is particularly the case with beta-lactam antibiotics such as ampicillin and amoxicillin, carbapenems such as imipenem and meropenem, and large molecular biologics such as some monoclonal antibodies and blood factors. In many cases, this instability arises from high concentration of drug in the unfrozen liquid remaining between ice crystals, and shifts in pH, ionic strength, dielectric strength and other physical properties of this unfrozen liquid.